Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.      

Do''s and don''t''s of percutaneous nephrostomy

Percutaneous nephrostomy procedures generally are safe. The associated mortality rate is approximately 0.04%, and the incidence of important complications is 5% (2-4). To minimize complications, certain precautions always should be followed. First, radiologists should perform a preprocedural evaluation of the patient, with correction of marked coagulopathy or thrombocytopenia before all but the most emergent procedures. Second, antibiotics should be administered routinely before nephrostomy drainage; the choice of antibiotics can be based on the specific patient's risk factors for bacteriuria. To minimize the risk of clinically important renal vascular damage, radiologists should do the following: 1. Always achieve adequate visualization of the calices. 2. Identify a posterior calix for puncture that will give access to the appropriate segment of the kidney for anticipated procedures and allow safe creation of a tract. 3. Puncture below the 11th rib (and preferably below the 12th rib when feasible). 4. Puncture the tip of a posterior calix from a 20 degrees-30 degrees, posterolateral oblique approach to avoid major blood vessels. 5. Make a single-wall puncture of the calix. 6. Perform exchange transfusion for opacification of the renal pelvis and calices during percutaneous nephrostomy procedures to minimize the risk of sepsis. Overdistention can increase the likelihood of sepsis or retroperitoneal contamination. 7. Inject contrast material via a catheter placed over a wire to confirm the intracollecting system location of the entry. 8. Avoid unnecessary (complicated, prolonged) procedures in an infected, obstructed system. 9. Use only self-retaining drainage catheters to minimize the risk of inadvertent catheter dislodgment. 10. Create large-bore tracts with a balloon dilation system. By contrast, radiologists should not do the following: 1. Puncture above the 11th rib (unless all other avenues of approach have been exhausted). 2. Lose access to an obstructed kidney once the kidney has been punctured. Placement of a "safety" wire for all complex manipulations is recommended. 3. Panic if excessive bleeding or evidence of adjacent organ injury is seen. Excessive bleeding usually can be stopped with tract tamponade by using a balloon catheter advanced through the tract or with placement of an appropriate-sized nephrostomy tube to occlude the tract. If active bleeding continues or recurs, arteriography should be considered. The quantity of bleeding can be monitored with sequential hematocrit measurements. Almost all renal artery injuries can be treated with minimally invasive procedures, such as selective embolization of the branch artery involved, and this will lead to infarction of only a small segment of kidney, with preservation of functioning renal parenchyma. Injury to an adjacent organ usually can be treated nonsurgically (21,23). The most commonly injured extrarenal abdominal organ is the colon (Fig 6). On occasion, a percutaneous nephrostomy needle may traverse the retroperitoneal segment of the colon, and this type of injury generally can be treated nonsurgically, as well (23). If the colon has been traversed, adequate urinary drainage should be ensured before the transcolonic nephrostomy catheter is removed (so that a nephrocolonic fistula is not maintained). This can be done by placing a ureteral stent and a bladder catheter (18). Once adequate urinary drainage is provided, the nephrostomy catheter can be withdrawn into the colon and used as a percutaneous colostomy drain. The percutaneous colostomy tract should be allowed to mature for several days before this catheter is removed. In addition, appropriate antibiotics should be administered from the time a transcolonic tract is identified until the percutaneous tract has healed completely. Transthoracic entry can cause pneumothorax and pleural effusions. These should be treated only if they are large or cause symptoms (21). (ABSTRACT TRUNCATED)     

Hypospadias trends in two US surveillance systems

OBJECTIVE: Hypospadias is a common congenital anomaly, the cause of which is unknown. Unexplained increases in the rates of hypospadias occurred in five European countries in the 1970s and 1980s. We examined data from two birth defects surveillance systems in the United States for evidence of similar trends. METHODOLOGY: The Metropolitan Atlanta Congenital Defects Program (MACDP) provided birth prevalence rates from 1968 to 1993. The nationwide Birth Defects Monitoring Program (BDMP) provided rates from 1970 to 1993. MACDP data are population-based and could be categorized by the severity of the hypospadias. BDMP data allowed analysis of rate trends for the four census regions of the United States. RESULTS: Data from both surveillance systems showed an approximate doubling of hypospadias rates in the 1970s and 1980s. MACDP data showed that the rate of severe cases increased while the ratio of mild to severe cases decreased. BDMP data showed that hypospadias rates increased markedly in all four regions of the United States. CONCLUSIONS: The observed increases are unlikely to be attributable to increased sensitivity of the surveillance systems or the identification of more mild cases by physicians over time, because either trend would have increased rather than decreased the ratio of mild to severe cases. If real, these trends represent the largest number of cases and the first report of an increase in hypospadias rates outside of Europe. Additional investigation of a possible increase in hypospadias rates is warranted.     

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.      

The duration of phorbol-inducible ErbB2 tyrosine dephosphorylation parallels that of receptor endocytosis rather than threonine-686 phosphorylation: implications for the physiological role of protein kinase C in growth factor receptor signalling

Tumour cell growth may be accelerated by protein kinase C (PKC) agonists such as phorbol esters and receptor tyrosine kinases, but receptor tyrosine kinases are in turn desensitized to growth factors by PKC agonists. To clarify this apparent PKC bifunctionality, we have used phosphoantibodies to determine the relationship between PKC- dependent phosphorylation events affecting the ErbB2 oncoprotein in G8/DHFR 3T3 cells. Neither the kinetics nor the extent of phorbol- induced juxtamembrane domain (Thr686) phosphorylation vary directly with C-terminal (Tyr1222) dephosphorylation, with Tyr1222 continuing to be dephosphorylated long after Thr686 phosphorylation has also declined. Platelet-derived growth factor (PDGF) mimics the short-term effects of phorbol on Thr686 and Tyr1222 phosphorylation, and confocal microscopy reveals that both of these PKC agonists induce rapid internalization of PKC-modified ErbB2. Phorbol causes sustained cytoplasmic accumulation of PKC-phosphorylated receptors, however, whereas PDGF triggers the appearance of this ErbB2 subset only briefly. Metabolic labelling and co-precipitation studies fail to implicate heterologous molecules in either the tyrosine dephosphorylation or internalization of PKC-modified ErbB2. Taken in the context of earlier juxtamembrane domain mutagenesis studies, these findings indicate that phorbol-activated PKC may desensitize growth factor receptors to extracellular ligands solely by triggering sustained receptor internalization. We submit that PKC-dependent juxtamembrane domain phosphorylation represents a physiological mechanism for shortening the duration and enhancing the specificity of growth factor signalling by promoting internalization of liganded and unliganded receptors, respectively.      

Intracranial chondroma of the occipital lobe

A case report of an intracranial chondroma is discussed with emphasis on magnetic resonance imaging.